The present invention relates to a drug complex which is useful as a medicament. More specifically, the present invention relates to a drug complex in which a carboxy(C1-4)alkyldextran polyalcohol that is a polysaccharide derivative and a drug compound such as antineoplastic agents or anti-inflammatory agents are bound to each other via a spacer.
Antineoplastic agents, used for treatment of solid cancers such as lung cancer or digestive organ carcinomas and blood cancers such as leukemia, are systemically administered through routes of administration such as intravenous or oral administration, and then, are distributed to specific tumorous sites and inhibit or suppress the proliferation of cancer cells to exhibit their therapeutic efficacy. However, the systemically-administered antineoplastic agents are rapidly taken into livers and reticuloendothelial organs from blood, or rapidly excreted into urine, and accordingly, their blood concentrations may sometimes be lowered to allow the distribution into tumorous sites to be insufficient. In addition, common antineoplastic agents themselves have poor distribution-selectivity to tumorous sites (tumor selectivity), and therefore, the antineoplastic agents are uniformly distributed over various tissues and cells of the whole body, and act as cytotoxins also against normal cells and tissues, which results in problems of the appearance of adverse effects, e.g., emesis, pyrexia, or alopecia at an extremely high rate. Therefore, it has been desired to develop a means of efficiently and selectively distributing antineoplastic agents to tumorous sites.
As one of such means, a process was proposed in which an antineoplastic agent is bound to a polysaccharide polymer to delay the disappearance of the antineoplastic agent from blood and to enhance selectivity to tumor tissues. For example, Japanese Patent Publication (KOKOKU) No. (Hei) 7-84481/1995 discloses a drug complex in which daunorubicin, doxorubicin, mitomycin C, bleomycin or the like is introduced into a carboxymethylated mannoglucan derivative by means of a Schiff base or an acid amide bond. As the mannoglucan derivative in the invention, carboxymethylated mannoglucan polyalcohols are also used. However, mannoglucan derivatives are too much branched and have complicated structures, and accordingly, it has been difficult to obtain a product with uniform quality suitable for manufacturing medicaments.
In addition, International Patent Publication WO94/19376 discloses a drug complex in which a peptide chain (the number of amino acid residues: 1 to 8) is bound to a carboxyl group of a polysaccharide having carboxyl groups, and doxorubicin, daunorubicin, mitomycin C, bleomycin or the like is further bound by means of the peptide chain. As the polysaccharide having carboxyl groups, examples are given such as polysaccharides inherently having carboxyl groups in their structures (e.g., hyaluronic acid), and polysaccharides inherently having no carboxyl groups in their structures (e.g., pullulan, dextran, chitin, etc.) in which their hydroxyl groups are modified with carbonyl groups by introducing with carboxy(C1-4.,)alkyl groups or binding with a polybasic acid such as malonic acid or succinic acid by esterification. The drug complexes are structurally characterized in that a drug such as doxorubicin and the above-mentioned polysaccharide moiety are bound to each other by means of a spacer, and the complexes have higher antineoplastic activity compared to doxorubicin and reduced toxicity and adverse effects.
As for technologies relating to drug complexes utilizing polyalcoholized polysaccharide derivatives as drug delivery carriers, some reports are available, for example, xe2x80x9cResearches on polysaccharide-peptide-doxorubicin complexes-Correlations between stabilities of polysaccharide carriers in blood and their anti-neoplastic activitiesxe2x80x9d (Abstracts of 10th Meeting of the Japan Society of Drug-Delivery System, 279, 1994); xe2x80x9cResearches on polysaccharide-peptide-doxorubicin complexes Pharmacokinetics and anti-neoplastic activityxe2x80x9d (Abstracts of 9th Annual Meeting of Japanese Society for the study of xenobiotics, 292, 1994); Abstracts of 19th Seminar of Trends in Research and Development (held by The Organization for Drug A D R Relief, RandD Promotion and Product Review), Dec. 9, 1995; and xe2x80x9cResearches on drug delivery to a tumor tissue by polysaccharide carriersxe2x80x9d (Abstracts of 12th Colloid and Interface Technology Symposium, The Chemical Society of Japan, 51, 1995).
An object of the present invention is to provide a drug complex capable of site-selectively delivering an active ingredient such as antineoplastic agents or anti-inflammatory agents to tumorous sites or the like. More specifically, the object of the present invention is to provide a drug complex which contains a drug compound such as antineoplastic agents or anti-inflammatory agents as a partial structure and can be retained in blood for a long period of time, and furthermore, can site-selectively deliver the drug compound to tumorous sites or inflammatory sites. In addition, another object of the present invention is to provide a method for preparing the drug complexes having the aforementioned features.
In order to achieve the foregoing object, the present inventors attempted to improve the drug complex disclosed in the International Patent Publication WO94/19376. As a result, they found that, when a dextran derivative obtained by the carboxy(C1-4)alkylation of a polyalcoholized dextran is used as a polysaccharide moiety instead of the polysaccharides having carboxyl groups, high concentration of the medicament was retained for a long period of time after administration, and site-selectivity to tumorous sites or inflammatory sites can significantly be improved. They also found that, in these compounds, the main efficacy such as antineoplastic activity is remarkably enhanced, whereas toxicity is reduced. The present invention was achieved on the basis of these findings.
The present invention thus provides a drug complex characterized in that a carboxy(C1-4)alkyldextran polyalcohol and a residue of a drug compound are bound to each other by means of a spacer comprising an amino acid or a spacer comprising peptide-bonded 2 to 8 amino acids. According to other embodiments of the present invention, there are provided a medicament comprising the aforementioned drug complex; and a pharmaceutical composition comprising the aforementioned drug complex as an active ingredient, for example, preparations for injection or drip infusion in the form of lyophilized products filled in vials. Furthermore, according to another embodiment of the present invention, a method for preparing the aforementioned drug complex is provided.
As preferred embodiments of the aforementioned invention, there are provided the above drug complex characterized in that the dextran polyalcohol that constitutes the carboxy(C1-4)alkyldextran polyalcohol is a dextran polyalcohol which is obtained by treating a dextran under conditions that enable substantially complete polyalcoholization; the above drug complex wherein the carboxy(C1-4)alkyldextran polyalcohol is carboxymethyldextran polyalcohol; the above drug complex wherein the drug compound is an antineoplastic agent or an anti-inflammatory agent; the above drug complex wherein the drug compound is an antineoplastic agent which concentration-dependently exhibits antineoplastic activity (an antineoplastic agent exhibiting more potent antineoplastic activity at a higher concentration: sometimes referred to as a concentration-dependent type antineoplastic agent in the present specification); the above drug complex wherein the drug compound is an antineoplastic agent which time-dependently exhibits antineoplastic activity (an antineoplastic agent exhibiting more potent antineoplastic activity at longer working times: sometimes referred to as a time-dependent type antineoplastic agent in the present specification); and the above drug complex wherein the antineoplastic agent is doxorubicin or (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo[de]pyrano[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13(9H, 15H)-dione.
In addition, as also preferred embodiments, there are provided the above drug complex wherein the spacer is a dipeptide represented by -X-Z-[the symbol xe2x80x9c-X-Z-xe2x80x9d means a residue which consists of a dipeptide that is formed by peptide bonding of a hydrophobic amino acid (X) and a hydrophilic amino acid (Z) being at the N-terminal side and the C-terminal side, respectively, and whose one hydrogen atom and one hydroxyl group are removed from the amino group at the N-terminus and the carboxyl group at the C-terminus, respectively], or wherein the spacer contains the dipeptide as a partial peptide sequence; the above drug complex wherein the hydrophobic amino acid is phenylalanine and the hydrophilic amino acid is glycine; the above drug complex wherein the spacer is (N-terminus)-Gly-Gly-Phe-Gly-; and the above drug complex wherein an introduced amount of the residue of the antineoplastic agent is in the range of from 1 to 15% by weight, preferably from 3 to 10% by weight, and more preferably from 5 to 6% by weight.
As particularly preferred embodiments of the present invention, there are provided the above drug complex wherein N-terminus of a peptide represented by H2N-Gly-Gly-Phe-Gly-COOH is bound to a carboxyl group of carboxymethyldextran polyalcohol by means of an acid-amide bond and C-terminus of the peptide is bound to the 1-amino group of (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]-quinoline-10,13(9H,15H)-dione by means of an acid-amide bond; the above drug complex wherein the introduced amount of the (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b-]-quinoline-10,13(9H,15H)-dione residue is in the range of from 2 to 10% by weight; and the above drug complex wherein the carboxy(C1-4)alkyldextran polyalcohol is a carboxymethyldextran polyalcohol having a molecular weight in the range of from 5,000 to 500,000, preferably in the range of from 50,000 to 450,000, and more preferably in the range of from 200,000 to 400,000, and the degree of carboxymethylation per constitutive saccharide residue is in the range of from 0.01 to 2.0, preferably in the range of from 0.1 to 1.0, and more preferably in the range of from 0.3 to 0.5.
According to another aspect of the present invention, a drug delivery carrier comprising the carboxy(C1-4)alkyldextran polyalcohol is provided. According to preferred embodiments of this aspect of the invention, a molecular weight of the carboxy(C1-4)alkyldextran polyalcohol is in the range of from 5,000 to 500,000, preferably in the range of from 50,000 to 450,000, and more preferably in the range of from 200,000 to 400,000, and the degree of carboxymethylation per constitutive saccharide residue is in the range of from 0.01 to 2.0, preferably in the range of from 0.1 to 1.0, and more preferably in the range of from 0.3 to 0.5. Carboxymethyldextran polyalcohol is provided as the most preferred carrier. From another aspect of the invention, there is provided a use of a carboxy(C1-4)alkyldextran polyalcohol for the manufacture of a drug complex which contains the carboxy(C1-4)alkyldextran polyalcohol bound to the residue of a drug compound.
As preferred embodiments of the present invention, there are provided the use of the carboxy(C1-4)alkyldextran polyalcohol for the manufacture of a drug complex in which the residue of a drug compound and the carboxy(C1-4)alkyldextran polyalcohol are bound to each other by means of a spacer; and the use of the carboxy(C1-4)alkyldextran polyalcohol for the manufacture of a drug complex characterized in that the carboxy(C1-4)alkyldextran polyalcohol and the residue of a drug compound are bound to each other by means of a spacer comprising an amino acid or a spacer comprising peptide-bonded 2 to 8 amino acids.